CRBN_HUMAN
ID CRBN_HUMAN Reviewed; 442 AA.
AC Q96SW2; B2R6H4; C9IZA9; C9JAH6; Q6AI62; Q6NVZ0; Q9UHW4;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Protein cereblon;
GN Name=CRBN; ORFNames=AD-006;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-442.
RC TISSUE=Adrenal gland;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W.,
RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J.,
RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z.,
RA Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis
RT and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 64-250.
RC TISSUE=Fetal kidney;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP INVOLVEMENT IN MRT2, AND TISSUE SPECIFICITY.
RX PubMed=15557513; DOI=10.1212/01.wnl.0000146196.01316.a2;
RA Higgins J.J., Pucilowska J., Lombardi R.Q., Rooney J.P.;
RT "A mutation in a novel ATP-dependent Lon protease gene in a kindred with
RT mild mental retardation.";
RL Neurology 63:1927-1931(2004).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=17380424; DOI=10.1007/s11033-007-9077-3;
RA Xin W., Xiaohua N., Peilin C., Xin C., Yaqiong S., Qihan W.;
RT "Primary function analysis of human mental retardation related gene CRBN.";
RL Mol. Biol. Rep. 35:251-256(2008).
RN [8]
RP FUNCTION.
RX PubMed=18414909; DOI=10.1007/s10048-008-0128-2;
RA Higgins J.J., Hao J., Kosofsky B.E., Rajadhyaksha A.M.;
RT "Dysregulation of large-conductance Ca2+-activated K+ channel expression in
RT nonsyndromal mental retardation due to a cereblon p.R419X mutation.";
RL Neurogenetics 9:219-223(2008).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY,
RP IDENTIFICATION IN A DCX COMPLEX WITH DDB1; RBX1 AND CUL4A,
RP THALIDOMIDE-BINDING, UBIQUITINATION, AND MUTAGENESIS OF TYR-384 AND
RP TRP-386.
RX PubMed=20223979; DOI=10.1126/science.1177319;
RA Ito T., Ando H., Suzuki T., Ogura T., Hotta K., Imamura Y., Yamaguchi Y.,
RA Handa H.;
RT "Identification of a primary target of thalidomide teratogenicity.";
RL Science 327:1345-1350(2010).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-25, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [11]
RP FUNCTION, AND MISCELLANEOUS.
RX PubMed=24328678; DOI=10.1111/bjh.12708;
RA Gandhi A.K., Kang J., Havens C.G., Conklin T., Ning Y., Wu L., Ito T.,
RA Ando H., Waldman M.F., Thakurta A., Klippel A., Handa H., Daniel T.O.,
RA Schafer P.H., Chopra R.;
RT "Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells
RT by inducing degradation of T cell repressors Ikaros and Aiolos via
RT modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).";
RL Br. J. Haematol. 164:811-821(2014).
RN [12]
RP FUNCTION, INTERACTION WITH DDB1, AND UBIQUITINATION.
RX PubMed=25043012; DOI=10.1038/nature13527;
RA Fischer E.S., Bohm K., Lydeard J.R., Yang H., Stadler M.B., Cavadini S.,
RA Nagel J., Serluca F., Acker V., Lingaraju G.M., Tichkule R.B.,
RA Schebesta M., Forrester W.C., Schirle M., Hassiepen U., Ottl J., Hild M.,
RA Beckwith R.E., Harper J.W., Jenkins J.L., Thoma N.H.;
RT "Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with
RT thalidomide.";
RL Nature 512:49-53(2014).
RN [13]
RP FUNCTION, AND MUTAGENESIS OF 419-ARG--LEU-442.
RX PubMed=29530986; DOI=10.1523/jneurosci.2081-17.2018;
RA Choi T.Y., Lee S.H., Kim Y.J., Bae J.R., Lee K.M., Jo Y., Kim S.J.,
RA Lee A.R., Choi S., Choi L.M., Bang S., Song M.R., Chung J., Lee K.J.,
RA Kim S.H., Park C.S., Choi S.Y.;
RT "Cereblon Maintains Synaptic and Cognitive Function by Regulating BK
RT Channel.";
RL J. Neurosci. 38:3571-3583(2018).
RN [14]
RP FUNCTION, AND INTERACTION WITH ILF2.
RX PubMed=33009960; DOI=10.1007/s10930-020-09918-9;
RA Lian Q., Gao Y., Li Q., He X., Jiang X., Pu Z., Xu G.;
RT "Cereblon Promotes the Ubiquitination and Proteasomal Degradation of
RT Interleukin Enhancer-Binding Factor 2.";
RL Protein J. 39:411-421(2020).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 48-428 IN COMPLEX WITH DDB1;
RP S-LENALIDOMIDE AND ZINC, FUNCTION, INTERACTION WITH DDB1, DOMAIN,
RP MUTAGENESIS OF TRP-386, AND MISCELLANEOUS.
RX PubMed=25108355; DOI=10.1038/nsmb.2874;
RA Chamberlain P.P., Lopez-Girona A., Miller K., Carmel G., Pagarigan B.,
RA Chie-Leon B., Rychak E., Corral L.G., Ren Y.J., Wang M., Riley M.,
RA Delker S.L., Ito T., Ando H., Mori T., Hirano Y., Handa H., Hakoshima T.,
RA Daniel T.O., Cathers B.E.;
RT "Structure of the human cereblon-DDB1-lenalidomide complex reveals basis
RT for responsiveness to thalidomide analogs.";
RL Nat. Struct. Mol. Biol. 21:803-809(2014).
RN [16]
RP INVOLVEMENT IN MRT2, AND VARIANT MRT2 ARG-391.
RX PubMed=28143899; DOI=10.1136/jmedgenet-2016-104117;
RA Sheereen A., Alaamery M., Bawazeer S., Al Yafee Y., Massadeh S., Eyaid W.;
RT "A missense mutation in the CRBN gene that segregates with intellectual
RT disability and self-mutilating behaviour in a consanguineous Saudi
RT family.";
RL J. Med. Genet. 54:236-240(2017).
CC -!- FUNCTION: Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3
CC protein ligase complex that mediates the ubiquitination and subsequent
CC proteasomal degradation of target proteins, such as MEIS2 or ILF2
CC (PubMed:33009960). Normal degradation of key regulatory proteins is
CC required for normal limb outgrowth and expression of the fibroblast
CC growth factor FGF8 (PubMed:20223979, PubMed:24328678, PubMed:25043012,
CC PubMed:25108355). Maintains presynaptic glutamate release and
CC consequently cognitive functions, such as memory and learning, by
CC negatively regulating large-conductance calcium-activated potassium
CC (BK) channels in excitatory neurons (PubMed:18414909, PubMed:29530986).
CC Likely to function by regulating the assembly and neuronal surface
CC expression of BK channels via its interaction with KCNT1
CC (PubMed:18414909). May also be involved in regulating anxiety-like
CC behaviors via a BK channel-independent mechanism (By similarity).
CC {ECO:0000250|UniProtKB:Q8C7D2, ECO:0000269|PubMed:18414909,
CC ECO:0000269|PubMed:20223979, ECO:0000269|PubMed:24328678,
CC ECO:0000269|PubMed:25043012, ECO:0000269|PubMed:25108355,
CC ECO:0000269|PubMed:29530986, ECO:0000305}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:20223979, ECO:0000305|PubMed:25108355}.
CC -!- SUBUNIT: Interacts with KCNT1 (By similarity). Component of a DCX
CC (DDB1-CUL4-X-box) protein ligase complex, at least composed of CRBN,
CC CUL4A, DDB1 and RBX1. Interacts directly with DDB1 (PubMed:25043012,
CC PubMed:25108355). Interacts (in pomalidomide-bound form) with IKZF1 and
CC IKZF3 (PubMed:24328678). Interacts with ILF2 (PubMed:33009960).
CC {ECO:0000250|UniProtKB:Q56AP7, ECO:0000269|PubMed:20223979,
CC ECO:0000269|PubMed:24328678, ECO:0000269|PubMed:25043012,
CC ECO:0000269|PubMed:25108355, ECO:0000269|PubMed:33009960}.
CC -!- INTERACTION:
CC Q96SW2; Q96A83-2: COL26A1; NbExp=3; IntAct=EBI-2510250, EBI-21553822;
CC Q96SW2; P48729: CSNK1A1; NbExp=3; IntAct=EBI-2510250, EBI-1383726;
CC Q96SW2; Q16531: DDB1; NbExp=3; IntAct=EBI-2510250, EBI-350322;
CC Q96SW2; O14901: KLF11; NbExp=3; IntAct=EBI-2510250, EBI-948266;
CC Q96SW2; Q8IVT2: MISP; NbExp=3; IntAct=EBI-2510250, EBI-2555085;
CC Q96SW2; Q9P286: PAK5; NbExp=4; IntAct=EBI-2510250, EBI-741896;
CC Q96SW2; D3DTS7: PMP22; NbExp=3; IntAct=EBI-2510250, EBI-25882629;
CC Q96SW2; Q93062: RBPMS; NbExp=3; IntAct=EBI-2510250, EBI-740322;
CC Q96SW2-2; Q16531: DDB1; NbExp=7; IntAct=EBI-10693561, EBI-350322;
CC Q96SW2-2; Q13422-7: IKZF1; NbExp=2; IntAct=EBI-10693561, EBI-11522367;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20223979}. Nucleus
CC {ECO:0000269|PubMed:20223979}. Membrane {ECO:0000250}; Peripheral
CC membrane protein {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96SW2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96SW2-2; Sequence=VSP_015209;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in brain.
CC {ECO:0000269|PubMed:15557513, ECO:0000269|PubMed:17380424}.
CC -!- DOMAIN: The CULT domain binds thalidomide and related drugs, such as
CC pomalidomide and lenalidomide. Drug binding leads to a change in
CC substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein
CC ligase complex, while no such change is observed in rodents.
CC {ECO:0000269|PubMed:25108355}.
CC -!- PTM: Ubiquitinated, ubiquitination is mediated by its own DCX protein
CC ligase complex. {ECO:0000269|PubMed:20223979,
CC ECO:0000269|PubMed:25043012}.
CC -!- DISEASE: Intellectual developmental disorder, autosomal recessive 2
CC (MRT2) [MIM:607417]: A disorder characterized by significantly below
CC average general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period. MRT2
CC patients display mild intellectual disability with a standard IQ ranged
CC from 50 to 70. IQ scores are lower in males than females. Developmental
CC milestones are mildly delayed. There are no dysmorphic or autistic
CC features. {ECO:0000269|PubMed:15557513, ECO:0000269|PubMed:28143899}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: Thalidomide was widely prescribed to pregnant women in
CC the late 1950s as a sedative and as treatment against morning sickness.
CC Thalidomide was found to be teratogenic, causing multiple birth
CC defects. Recently, thalidomide use has increased for the treatment of
CC multiple myeloma and erythema nodosum leprosum, a painful complication
CC of leprosy. Binding of pomalidomide and other thalidomide-related drugs
CC leads to a change in substrate specificity of the human DCX (DDB1-CUL4-
CC X-box) E3 protein ligase complex, and this is probably the underlying
CC cause of the teratogenic activity of thalidomide, possibly due to
CC abnormal regulation of the BMP and FGF8 signaling pathways
CC (PubMed:20223979). The thalidomide-induced change in substrate
CC specificity leads to decreased degradation of MEIS2 and other target
CC proteins and increased degradation of MYC, IRF4, IKZF1 and IKZF3, and
CC this is probably the reason for the anti-proliferative and
CC immunomodulatory effects of thalidomide and related drugs
CC (PubMed:25108355). Thalidomide is also teratogenic in chicken and
CC zebrafish, but not in mice. {ECO:0000305|PubMed:20223979,
CC ECO:0000305|PubMed:25108355}.
CC -!- SIMILARITY: Belongs to the CRBN family. {ECO:0000305}.
CC -!- CAUTION: Although it contains a Lon N-terminal domain also found in
CC proteases of the peptidase S16 family, it does not contain the ATP-
CC binding and catalytic domains, suggesting that it has no protease
CC activity. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF17211.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAG35471.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAG35471.1; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=A short story - Issue 117 of
CC May 2010;
CC URL="https://web.expasy.org/spotlight/back_issues/117";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AK027507; BAB55162.1; -; mRNA.
DR EMBL; AK312577; BAG35471.1; ALT_SEQ; mRNA.
DR EMBL; AC024060; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017419; AAH17419.1; -; mRNA.
DR EMBL; BC067811; AAH67811.1; -; mRNA.
DR EMBL; AF117230; AAF17211.1; ALT_FRAME; mRNA.
DR EMBL; CR627060; CAH10361.1; -; mRNA.
DR CCDS; CCDS2562.1; -. [Q96SW2-1]
DR CCDS; CCDS54547.1; -. [Q96SW2-2]
DR RefSeq; NP_001166953.1; NM_001173482.1. [Q96SW2-2]
DR RefSeq; NP_057386.2; NM_016302.3. [Q96SW2-1]
DR PDB; 4M91; X-ray; 1.10 A; B=229-240.
DR PDB; 4TZ4; X-ray; 3.01 A; C=48-428.
DR PDB; 5FQD; X-ray; 2.45 A; B/E=41-442.
DR PDB; 5HXB; X-ray; 3.60 A; C/Z=40-442.
DR PDB; 5V3O; X-ray; 3.20 A; C=40-442.
DR PDB; 6BN7; X-ray; 3.50 A; B=1-442.
DR PDB; 6BN8; X-ray; 3.99 A; B=1-442.
DR PDB; 6BN9; X-ray; 4.38 A; B=1-442.
DR PDB; 6BNB; X-ray; 6.34 A; B=1-442.
DR PDB; 6BOY; X-ray; 3.33 A; B=1-442.
DR PDB; 6H0F; X-ray; 3.25 A; B/E/H/K=41-442.
DR PDB; 6H0G; X-ray; 4.25 A; B/E=41-397.
DR PDB; 6UML; X-ray; 3.58 A; C=40-442.
DR PDB; 6XK9; X-ray; 3.64 A; C/Z=40-442.
DR PDB; 7BQU; X-ray; 1.90 A; A=318-426.
DR PDB; 7BQV; X-ray; 1.80 A; A=318-426.
DR PDB; 7LPS; X-ray; 3.78 A; B/E/H/K=47-436.
DR PDBsum; 4M91; -.
DR PDBsum; 4TZ4; -.
DR PDBsum; 5FQD; -.
DR PDBsum; 5HXB; -.
DR PDBsum; 5V3O; -.
DR PDBsum; 6BN7; -.
DR PDBsum; 6BN8; -.
DR PDBsum; 6BN9; -.
DR PDBsum; 6BNB; -.
DR PDBsum; 6BOY; -.
DR PDBsum; 6H0F; -.
DR PDBsum; 6H0G; -.
DR PDBsum; 6UML; -.
DR PDBsum; 6XK9; -.
DR PDBsum; 7BQU; -.
DR PDBsum; 7BQV; -.
DR PDBsum; 7LPS; -.
DR AlphaFoldDB; Q96SW2; -.
DR SMR; Q96SW2; -.
DR BioGRID; 119360; 193.
DR CORUM; Q96SW2; -.
DR DIP; DIP-53521N; -.
DR IntAct; Q96SW2; 41.
DR MINT; Q96SW2; -.
DR STRING; 9606.ENSP00000231948; -.
DR BindingDB; Q96SW2; -.
DR ChEMBL; CHEMBL3763008; -.
DR DrugBank; DB00480; Lenalidomide.
DR DrugBank; DB08910; Pomalidomide.
DR DrugBank; DB01041; Thalidomide.
DR DrugCentral; Q96SW2; -.
DR GuidetoPHARMACOLOGY; 3086; -.
DR TCDB; 8.A.162.1.1; the cereblon (crbn) family.
DR iPTMnet; Q96SW2; -.
DR PhosphoSitePlus; Q96SW2; -.
DR BioMuta; CRBN; -.
DR DMDM; 73918916; -.
DR EPD; Q96SW2; -.
DR jPOST; Q96SW2; -.
DR MassIVE; Q96SW2; -.
DR MaxQB; Q96SW2; -.
DR PaxDb; Q96SW2; -.
DR PeptideAtlas; Q96SW2; -.
DR PRIDE; Q96SW2; -.
DR ProteomicsDB; 78157; -. [Q96SW2-1]
DR ProteomicsDB; 78158; -. [Q96SW2-2]
DR Antibodypedia; 25089; 154 antibodies from 29 providers.
DR DNASU; 51185; -.
DR Ensembl; ENST00000231948.9; ENSP00000231948.4; ENSG00000113851.16. [Q96SW2-1]
DR Ensembl; ENST00000432408.6; ENSP00000412499.2; ENSG00000113851.16. [Q96SW2-2]
DR GeneID; 51185; -.
DR KEGG; hsa:51185; -.
DR MANE-Select; ENST00000231948.9; ENSP00000231948.4; NM_016302.4; NP_057386.2.
DR UCSC; uc003bpq.4; human. [Q96SW2-1]
DR CTD; 51185; -.
DR DisGeNET; 51185; -.
DR GeneCards; CRBN; -.
DR HGNC; HGNC:30185; CRBN.
DR HPA; ENSG00000113851; Low tissue specificity.
DR MalaCards; CRBN; -.
DR MIM; 607417; phenotype.
DR MIM; 609262; gene.
DR neXtProt; NX_Q96SW2; -.
DR OpenTargets; ENSG00000113851; -.
DR Orphanet; 88616; Autosomal recessive non-syndromic intellectual disability.
DR PharmGKB; PA134926851; -.
DR VEuPathDB; HostDB:ENSG00000113851; -.
DR eggNOG; KOG1400; Eukaryota.
DR GeneTree; ENSGT00390000016404; -.
DR HOGENOM; CLU_025648_1_1_1; -.
DR InParanoid; Q96SW2; -.
DR OMA; AYQMYDS; -.
DR PhylomeDB; Q96SW2; -.
DR TreeFam; TF106115; -.
DR PathwayCommons; Q96SW2; -.
DR Reactome; R-HSA-9679191; Potential therapeutics for SARS.
DR SignaLink; Q96SW2; -.
DR SIGNOR; Q96SW2; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 51185; 33 hits in 1120 CRISPR screens.
DR ChiTaRS; CRBN; human.
DR GeneWiki; Cereblon; -.
DR GenomeRNAi; 51185; -.
DR Pharos; Q96SW2; Tclin.
DR PRO; PR:Q96SW2; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q96SW2; protein.
DR Bgee; ENSG00000113851; Expressed in calcaneal tendon and 200 other tissues.
DR ExpressionAtlas; Q96SW2; baseline and differential.
DR Genevisible; Q96SW2; HS.
DR GO; GO:0031464; C:Cul4A-RING E3 ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl.
DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl.
DR GO; GO:1902607; P:negative regulation of large conductance calcium-activated potassium channel activity; IEA:Ensembl.
DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IEA:Ensembl.
DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IEA:Ensembl.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB.
DR CDD; cd15777; CRBN_C_like; 1.
DR Gene3D; 2.30.130.40; -; 1.
DR InterPro; IPR034750; CULT.
DR InterPro; IPR003111; Lon_prtase_N.
DR InterPro; IPR046336; Lon_prtase_N_sf.
DR InterPro; IPR015947; PUA-like_sf.
DR InterPro; IPR004910; Yippee/Mis18/Cereblon.
DR Pfam; PF02190; LON_substr_bdg; 1.
DR Pfam; PF03226; Yippee-Mis18; 1.
DR SMART; SM00464; LON; 1.
DR SUPFAM; SSF88697; SSF88697; 1.
DR PROSITE; PS51788; CULT; 1.
DR PROSITE; PS51787; LON_N; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant;
KW Intellectual disability; Membrane; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway; Zinc.
FT CHAIN 1..442
FT /note="Protein cereblon"
FT /id="PRO_0000076160"
FT DOMAIN 81..317
FT /note="Lon N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01123"
FT DOMAIN 318..426
FT /note="CULT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01124"
FT REGION 1..45
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 323
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT BINDING 326
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT BINDING 378
FT /ligand="(S)-thalidomide"
FT /ligand_id="ChEBI:CHEBI:61918"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT BINDING 380
FT /ligand="(S)-thalidomide"
FT /ligand_id="ChEBI:CHEBI:61918"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT BINDING 386
FT /ligand="(S)-thalidomide"
FT /ligand_id="ChEBI:CHEBI:61918"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT BINDING 391
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT BINDING 394
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25108355,
FT ECO:0007744|PDB:4TZ4"
FT MOD_RES 25
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 23
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_015209"
FT VARIANT 391
FT /note="C -> R (in MRT2; dbSNP:rs797045036)"
FT /evidence="ECO:0000269|PubMed:28143899"
FT /id="VAR_079409"
FT MUTAGEN 384
FT /note="Y->A: Abolishes thalidomide-binding without
FT affecting DCX protein ligase complex activity; when
FT associated with A-386."
FT /evidence="ECO:0000269|PubMed:20223979"
FT MUTAGEN 386
FT /note="W->A: Abolishes thalidomide-binding without
FT affecting DCX protein ligase complex activity; when
FT associated with A-384. Abolishes pomalidomide-induced
FT change in substrate specificity and abolishes pomalidomide-
FT induced decrease in cell viability that is brought about by
FT increased degradation of MYC, IRF4 and IKZF3."
FT /evidence="ECO:0000269|PubMed:20223979,
FT ECO:0000269|PubMed:25108355"
FT MUTAGEN 419..442
FT /note="Missing: Fails to rescue increased BK channel
FT activity and decreased probability of neurotransmission in
FT a mouse hippocampal neuron model."
FT /evidence="ECO:0000269|PubMed:29530986"
FT CONFLICT 229
FT /note="K -> R (in Ref. 2; AAH67811)"
FT /evidence="ECO:0000305"
FT CONFLICT 237
FT /note="L -> P (in Ref. 1; BAG35471)"
FT /evidence="ECO:0000305"
FT CONFLICT 292
FT /note="D -> G (in Ref. 1; BAG35471)"
FT /evidence="ECO:0000305"
FT CONFLICT 330
FT /note="E -> G (in Ref. 1; BAG35471)"
FT /evidence="ECO:0000305"
FT TURN 51..53
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 54..56
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 58..60
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 78..83
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 96..101
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 104..115
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 119..127
FT /evidence="ECO:0007829|PDB:5FQD"
FT TURN 128..131
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 132..149
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 152..172
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 174..176
FT /evidence="ECO:0007829|PDB:6H0F"
FT STRAND 178..184
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 195..197
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 200..205
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 215..219
FT /evidence="ECO:0007829|PDB:6H0F"
FT HELIX 220..231
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 233..237
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 238..240
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 242..246
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 250..262
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 269..272
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 277..286
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 292..299
FT /evidence="ECO:0007829|PDB:5FQD"
FT HELIX 304..317
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 320..323
FT /evidence="ECO:0007829|PDB:7BQV"
FT TURN 324..326
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 330..333
FT /evidence="ECO:0007829|PDB:7BQV"
FT HELIX 334..336
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 341..343
FT /evidence="ECO:0007829|PDB:7BQU"
FT STRAND 345..350
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 356..363
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 367..375
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 384..391
FT /evidence="ECO:0007829|PDB:7BQV"
FT TURN 392..394
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 397..406
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 410..418
FT /evidence="ECO:0007829|PDB:7BQV"
FT HELIX 419..421
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 422..424
FT /evidence="ECO:0007829|PDB:7BQV"
FT STRAND 427..429
FT /evidence="ECO:0007829|PDB:5FQD"
FT STRAND 432..434
FT /evidence="ECO:0007829|PDB:6H0F"
SQ SEQUENCE 442 AA; 50546 MW; 90DF77D98A8BEAA8 CRC64;
MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL
GADMEEFHGR TLHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF
AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI GRQRFKVLEL RTQSDGIQQA
KVQILPECVL PSTMSAVQLE SLNKCQIFPS KPVSREDQCS YKWWQKYQKR KFHCANLTSW
PRWLYSLYDA ETLMDRIKKQ LREWDENLKD DSLPSNPIDF SYRVAACLPI DDVLRIQLLK
IGSAIQRLRC ELDIMNKCTS LCCKQCQETE ITTKNEIFSL SLCGPMAAYV NPHGYVHETL
TVYKACNLNL IGRPSTEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS
ALLPTIPDTE DEISPDKVIL CL
